The plant extract Ginkgo biloba EGb761 (ginkgo extract) counteracts the effects of a variety of neurological disorders, including Alzheimer's disease, in standardized neurophysiological tests. The cellular mechanisms underlying these beneficial effects, however, remain unclear. The proposed research focuses on elucidating the molecular mechanisms underlying Ginkgo biloba extract EGb761's ability to protect the brain from oxidative stress-induced cytotoxicity. Preliminary evidence indicates that Ginkgo biloba extract EGb761 activates the antioxidant response element (ARE) and also induces transthyretin (TTR) expression. Both ARE activation and increased expression of TTR have been associated with neuroprotection from oxidative stress and beta-amyloid toxicity, respectively. Preliminary experiments also demonstrate that the increase in TTR levels by ginkgo extract is not dependent on ARE activation suggesting that ginkgo extract contains molecules capable of activating two independent neuroprotective pathways. Thus, the goal of this research project is to detail ginkgo extract's effects on ARE activation and TTR induction. The specific aims of this proposl are: (I) Examine the signaling pathways and neuroprotective effects afforded by Ginkgo biloba extract EGb761 manifest through ARE activation and/or transthyretin expression in human cell lines and transgenic reporter mouse primary cultures; (II) In collaboration with Dr. Peter Schultzs' lab at The Scripps Research Institute, identify the chemical components of the ginkgo extract that activate these neuroprotective pathways and examine the in vivo effects of the purified component with regards to ARE activation and transthyretin expression.